17alpha-acetyl-delta-androstadiene-11beta, 17beta-diol-3-one and preparation thereof



United States iatented Nov. 7, 1961 Melting point: l06197 0.

is a valuable intermediate in the manufacture of therapeutic substancesand has itself particular pharmacodynamic properties.

Said compound of Formula I is prepared according to the presentinvention by adding one molecule of water to 17cc ethynyl Aandrostadiene 115,175 diol- 3-one of Formula II:

on uzon Said hydration reaction is preferably effected in the presenceof the mercury salt of p-toluene sulfonamide.

The 17a ethynyl A androstadiene 113,175- diol-3-one used as startingmaterial is prepared by condensing n -androstadiene-ll1,17-trione withacetylene in the presence of alcoholates or amides of alkali metals oralkaline earth metals, such as the potassium, lithium, or calciumalcoholates or amides in an inert solvent. Condensation with acetylenemay also be effected in the presence of liquid ammonia, whereby onaddition of the alkali or alkaline earth metals the metal amides areproduced in situ. After acetylene addition is completed, the reactionmixture is acidified and 11-keto-17u-ethynyln -androstadieneolone isextracted by means of a solvent and purified by recrystallization. Inorder to obtain the corresponding llfi-hydroxylated compound, the3-monosemicarbazone of said 3,11-diketone is formed and is reduced in asolvent, preferably in aqueous tetrahydrofuran.

:According to the present invention the compound of Formula I isprepared by boiling the ethynyl compound of Formula H in alcoholicsolution in the presence of the mercury salt of p-toluene sulfonamidewhich acts as a catalyst. After cooling, the desired steroid compound of'Formula I is isolated.

The following examples serve to illustrate the present inventionWithout, however, limiting the same thereto.

The melting points given in said examples are instantaneous meltingpoints, determined on the Maquenne block.

EXAMPLE 1 Preparation of 1 7oc-acetyZ-A -androstzrdiene-11{3,17,8-di0l-3-0ne of Formula I 2 g. of 17a-ethynyl-n -androstadiene-1l[3,l7B-diol-3-one of Formula II, are refluxed in 200 cc. of alcohol which contains 2g. of the mercury salt of p toluene sulfonamide. Heating under reflux iscontinued with stirring for 8 hours. After cooling, the catalyst isfiltered off and is extracted successively with alcohol, methylenechloride, and ethyl acetate. The crude compound of Formula I is obtainedby distilling to dryness the combined extracts and alcoholic filtrate.Said crude compound is dissolved in ethyl acetate, treated with animalcharcoal, and filtered. On distilling the filtrate to dryness, 1 g. ofthe compound of Formula I is obtained. Its melting point, onrecrystallization from ethyl acetate, is l96197 (3.; its opticalrotation [a] =+64i5 (concentration: 0.5% in chloroform). The compound issoluble in alcohol, acetone, chloroform, and ethyl acetate, sparinglysoluble in benzene or ether, and insoluble in water and dilute aqueousacids or alkalies.

Analysis.-C H O molecular weight: 344.4. Oalculated: 73.22% C; 8.19% H;18.58% 0. Found: 73.4% C; 8.1% H; 18.9% 0.

This compound has not been previously described in the literature.

EXAMPLE 2 On heating 200 mg. of said compound of Formula I to 200 C. for5 minutes, 126 mg. (corresponding to a yield of 63%) of 17a-methyl-AD-homoandrostadiene- 1lB,l7fi-diol-3,l7a-dione are obtained. Its meltingpoint is 225 C. and its optical rotation [u] =|32i5 (:concentration:0.5%in chloroform).

This compound, which has not been previously described in theliterature, is obtained in the form of colorless crystals, soluble inalcohol, acetone, chloroform, and ethyl acetate, sparingly soluble inbenzene, and insoluble in water, dilute aqueous acids and alkalies, andether.

Analysis.-C H O molecular weight: 344.4. Calculated: 73.22% 'C; 8.19% H;18.58% 0. Found: 73.0% C; 8.1% H; 18.8% 0.

Its infra-red spectrum shows the presence of the D- homo ring.

EXAMPLE 3 The starting material is obtained by proceeding as follows:

A solution of 2.35 g. of A -dehydro adrenosterone (prepared as describedin J. Am. Chem. Soc., vol. 77 (1955), p. 4781) in 30 cc. of dioxane issaturated with acetylene; to this solution there are added 12 cc. of asolution obtained from 9.5 g. of potassium metal, cc. of tertiary amylalcohol and 30 cc. of benzene. This addition produces a bright,brick-red color and causes formation of a reddish-brown precipitate.Purified acetylene is passed through the mixture for 2 /2 hours,whereupon 10 cc. of 50% acetic acid are added. The solution turns paleyellow. Precipitation is accomplished by adding 300 cc. of water andextraction is carried out with ch10- roform. The chloroform layer iswashed with water, dried over magnesium sulfate, and filtered. Thechloroform extract is treated with charcoal and is evaporated todryness. The residue is treated with ether and filtered and Washed witha very small amount of icecold alcohol and then with ether. Afterdrying, 1.64 g. of an almost pure product of a very pale yellow color,having a melting point of 250-252 C. are obtained. In order to purifythis product, it is dissolved in 40 cc. of absolute alcohol, thesolution is concentrated to cc., and the concentration is permitted tocrystallize. After drying, washing the residue with ice-cold alcohol,and again drying, there are obtained 1.23 g. of the pure product, havinga melting point of 253 C., and an optical rotation [a] =-{-80i2(concentration: 1% in dioxane). The compound is solvated, it contains0.7% of alcohol which it loses when heated to 135 C. It is soluble in 25volumes of hot alcohol, in acetone, fairly well soluble in chloroform,almost insoluble in ether, and insoluble in water and in dilute aqueousacids and alkalies.

Analysis.C H O molecular weight: 324. Calculated: 77.75% C; 7.45% H.Found: 77.6% C; 7.4% H.

Upon heating to 200 C., this compound sublimates into colorless needles.

1 g. of said l1-keto-17ix-ethynyl-A -androstadiene- 17fl-0l-3-oneobtained, having a melting point of 252 C., is heated at 60 C. with 60cc. of a solution of 5% semicarbazide acetate in 90% alcohol for 14hours. After cooling, the precipitate is filtered, the residue is washedwith sold alcohol, and dried. About 1 g. of the 3-semicarbazone isobtained Which is sufficiently pure for the subsequent reduction step.

0.90 g. of said semicarbozone are dissolved in a mixture of 20 cc. oftetrahydrofuran and 2 cc. of water. The solution is cooled to 5 C., and2 g. of potassium boronhydride dissolved in cc. of water are added. Twolayers form rapidly. The mixture is heated to 45 C. for 4 /2 hours whilestirring vigorously, is neutralized by adding 10 cc. of 50% acetic acidand is concentrated in a vacuum at a temperature below 50 C. A productseparates which is gummy when hot and becomes pulverulent upon cooling.After washing with water and drying, 0.9 g. of a pale beige powder areobtained, constituting the crude 3-semicarbazone, which is directlyhydrolyzed to 1lfi-hydroxy-17u-ethynyl-A -androstadiene- 17 3-ol-3-oneby heating to 90 C. for 1 /2 hours with 6 cc. of pyruvic acid. Completedissolution takes place and the reaction mixture is poured into anaqueous solution of sodium bicarbonate in order to neutralize thepyruvic acid. After filtering, washing with water, drying, dissolving in2 cc. of methanol, filtering hot, and concentrating to about one-fifthof the orginal volume, 11,8- hydroxy 17a ethynyl-A-androstadiene-17/3-ol-3-one is obtained, which crystallizes in bigprisms of a very pale yellow color and has a melting point of 280 C. Itsublimates from 250 C. on in colorless needles. It is soluble inmethanol, insoluble in water, ether, and benzene. It can, moreover, beidentified by its U.V. spectrum (A max. 244 III/1.; e=l3,0). Theinfra-red spectrum shown that the keto group in position 11 hasdisappeared while the diene ketone function 1,4 subsists.

Of course, many changes and variations in the reaction conditions,temperature and duration, in the solvents used, in the manner in whichthe reaction products are worked up and purified, and the like may bemade by those skilled in the art in accordance with the principles setforth herein and in the claims annexed hereto.

The new 17a-acetyl-A -androstadiene-11,3,17,8-diol-3- one as Well as the17ot-methyl-A -D-homoandrostadiene- 11B,17,8-diol-3,l7a-dione accordingto the present invention have proved to be of great value in thetreatment of hyperlipemic disease.

We claim:

1. 17a-acetyl-A -androstadiene-1 l,8,17 8-diol-3-one.

2. In a process of producing 17u-acetyl-A-androstadiene-l1fl,17,8-diol-3-one, the step which comprises heatingunder reflux a solution of 17et-ethynyl-A-androstadiene-l1,8,17,6-diol-3-one in ethanol with the addition of themercury salt of p-toluene sulfonamide as hydrating catalyst until onemole of Water is added to the ethynyl bond.

References Cited in the file of this patent UNITED STATES PATENTS2,767,199 Djerassi et al Oct. 16, 1956

1. 17A-ACETYL-$1,4-ANDROSTADIENE-11B,17B-DIOL-3-ONE.